Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
The preparation of compounds of Formula I, for example, the compounds of Formula III, has been described in Published U.S. Patent Application No. 2004-0209878 A1, filed on Feb. 11, 2004 (the '878 publication), which is incorporated herein by reference.
wherein R1 is a linear, branched, or cyclic alkyloxy functional group of the structure (—R2a—OH), R2a is a linear, branched or cyclic alkylene group, R2 is a linear, branched or cyclic alkyl group, and R3 is an alkylene-heterocycle, for example, the 3-methylene-pyridine-N-oxide substituent shown in the structure of Formula III. These compounds are believed to have pharmaceutical activity as compounds having cyclin-dependent kinase inhibitor (CDK inhibitor) properties.
As described in the '878 publication, the compounds of Formula I can be prepared through the general routes described below in Scheme I.
Where R1, R2, and R3 are as defined above, R4 and R7 are H, or R2 and R5 and R6 are taken together to form an alkyl heterocycle, for example, pyrimidin-1-yl, optionally substituted on any carbon with a linear, branched, or cyclic alkyl, which is optionally substituted with hydroxide.
One of these inhibitor compounds of particular interest for its CDK inhibiting activity is the compound of Formula II.
As described in detail in the '878 publication, in Example 500, on pages 334 to 343, the compound of Formula II can be synthesized in accordance with Scheme II:

In the second amination reaction of Step 3 of the Scheme II synthesis, the chiral alcohol reagent (S)2-piperidin-2-yl ethanol (compound G1) is reacted with (5-Chloro-3-ethyl-pyrazolo[1,5-a]pyridin-7-yl)-(1-oxy-pyridin-3-ylmethyl)-amine (compound G) to yield the compound of Formula II.
The chiral alcohol (G1) is commercially available as a mixture of R and S isomers. Resolution of these isomers has been accomplished by complexing the alcohol with d-10-champhorsulfonic acid (the compound of the structure of Formula G2a) and crystallizing the complexed alcohol from ethanol in accordance with a literature procedure published in the Journal of the American Chemical Society, 82, pp 2613 to 2616 (1960).
Resolution of 2-piperidin-2-yl ethanol by this method has also been reported in the Journal of Medicinal Chemistry, 45, p 2432, Bioorganic and Medicinal Chemistry Letters, 10, 1732 (2000), Chirality, 10, p 434 (1998), and the Journal of the Chemistry Society, Perkin Transactions I, 63, p 2903 (1994). This published procedure generally provides the alcohol in a yield of less than 17% based on the mixed isomer starting alcohol, and typically produces the desired isomer in yields of less than 10% based on the starting alcohol. When using this procedure, generally numerous sequential recrystallizations are required to achieve enantiomeric purity of 95% enantiomeric excess (ee) or more, which diminishes the yield of the desired isomer. Enantiomeric purity is calculated by subtracting the weight of the minority isomer from the weight of the predominant isomer present in a sample, and dividing the difference by the sum of the minority and predominant isomers present in the sample. Accordingly, a sample having 97.5 wt. % of the S isomer and 2.5 wt. % of the R isomer has an enantiomeric purity of 95% ee. In the synthesis of CDK inhibitor compounds described above, it is desirable to utilize the desired isomer of piperidine-ethanol starting materials having more than about 97% ee purity.